1,2-oxazinyl phenyl alkanoic acids

ABSTRACT

THE COMPOUNS ARE OF THE CLASS OF (P-(3,6-DIHYDRO-2H1,2-OXAZIN- 2-YL)-PHENYL)-ALKANOIC ACIDS, THE METHYL AND ETHYL ESTERS THEREOF, AS WELL AS THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF AND HAVE ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY; THE COMPOUNDS ARE ACTIVE INGREDIENTS OF PHARMACEUTICAL COMPOSITIONS AND ARE USEFUL FOR ALLEVIATING PAIN AND TREATING INFLAMMATORY DISEASES IN MAMMALS;AN ILLUSTRATIVE EMBODIMENT IS (P-3,6-DIHYDRO-2H-1,2-OXAZIN2-YL)-PHENYL)-ACETIC ACID.

United States Patent 3,585,676 Patented June 22, 1971 3,586,676 1,2-XAZINYL PHENYL ALKANOIC ACIDS Rolf Denss, Basel, Switzerland, Niels Clauson-Kaas,

Farum, Denmark, and Franz Ostermayer, Riehen, Switzerland, assignors to Geigy Chemical Corporation, Ardsley, N.Y.

No Drawing. Filed Apr. 22, 1969, Ser. No. 818,407 Claims priority, application Switzerland, Apr. 29, 1968, 6,375/ 68 Int. Cl. (307d 87/12 US. Cl. 260244R 4 Claims ABSTRACT OF THE DISCLOSURE The compounds are of the class of [p-(3,6-dihydro-2H- 1,2-oxazin-2-yl)-phenyl]-alkanoic acids, the methyl and ethyl esters thereof, as well as the pharmaceutically acceptable salts thereof and have analgesic and anti-inflammatory activity; the compounds are active ingredients of pharmaceutical compositions and are useful for alleviating pain and treating inflammatory diseases in mammals; an illustrative embodiment is [p-(3,6-dihydro-2H-1,2-oxazin- 2-yl)-phenyl]-acetic acid.

DETAILED DESCRIPTION The present invention concerns 1,2-oxazinyl phenyl alkanoic acid derivatives, pharmaceutical compositions comprising these compounds and a pharmaceutical carrier and methods of alleviating pain and treating inflammatory discases in mammals comprising administering them.

More particularly, the present invention concerns compounds of the formula 2 wherein R is hydrogen, methyl or ethyl,

R is hydrogen or halogen up to the atomic number 35,

and

R is hydrogen, methyl or ethyl,

and the pharmaceutically acceptable salts of the compounds of Formula I, wherein R is hydrogen.

In the compounds of Formula I and the starting materials mentioned below, R as halogen up to the atomic number 35, can be fluoro, chloro or bromo.

Compounds of Formula I, wherein R is methyl or ethyl have an optically active carbon atom giving rise to enantiomeric forms. Embraced by the present invention the racemates as well as the single enantiomers.

A preferred subclass are the compounds of Formula I wherein R is hydrogen or methyl, R is hydrogen or chloro and R is hydrogen, and the pharmaceutically acceptable salts thereof.

Preferred members of the compounds of Formula I are [p-(3,6-dihydro-2H-1,2-oXazin-2-yl)-phenyl]-acetic acid, 2 [3 chloro 4 (3,6 dihydro 2H 1,2 oxazin 2 yl)-phenyl]-propionic acid and the pharmaceutically acceptable salts thereof.

The compounds of the present invention were found to have valuable pharmacological properties, in particular analgetic, anti-inflammatory and anti-pyretic activity, combined with a favorable therapeutic index. The pharmacological activity of the compounds of the invention is determined in various standard tests with experimental animals.

The analgesic activity is demonstrated in the writhing test in mice. This test is described by E. Siegmund, R.

Cadmus and G. Lu, Proc. Soc. Exp. Biol. Med. 95, 729 (1957). The amount of test substance is determined preventing in the test animals the syndrome produced by intraperitoneal injection of Z-phenyl-1,4-benzoquinone. Excellent results are obtained by oral administration of 10 mg./kg. of bodyweight of 2-[3-chloro-4-(3,6-dihydro-2H- l,2-oxazin-2-yl)phenyl]propionic acid.

As an example of the use as anti-inflammatory agent, the use of 2-[3-chloro-4-(3,6-dihydro-2H-1,2-oxazin-2-yl) phenyl]-propionic acid in bolus alba induced edema in the rat paw is described. The test used is that described by G. Wilhelmi, Jap. Iourn. Pharmac. 15, 190 (1965). The compound under investigation is administered to rats perorally through an esophageal sound. One hour thereafter, bolus alba edema is induced by subcutaneous injection of 0.1 ml. of a 10% suspension of finely sieved bolus alba in tragacanth into the plantar region of the right hand paw of the rats. Another group of rats having not obtained the test compound, but the bolus alba, serves as control group. Each group consists of male albino rats weighing about 110 to about 130 g. The intensity of the swelling of the rats paw is determined 5 hours after the bolus alba injection, by measuring the weight differences of the unswollen left paws and the swollen right paws. Thus it is determined that 2-[3-chloro 4-(3,6-dihydro-2H- 1,2-oxazin-2-yl -phenyl] -propionic acid administered in a dosage of about mg./kg. of bodyweight significantly inhibits the formation of the bolus alba edema indicating a pronounced anti-inflammatory activity.

Similar analgesic and anti-inflammatory activities are found with other compounds of the invention.

The toxicity of the compounds of the invention on oral administration is of favorable low order.

The new l,2-oxazinylphenylalkanoic acids and esters of Formula I and their pharmaceutically acceptable salts with inorganic and organic bases are suitable as active ingredients for pharmaceutical compositions, which can be administered orally, rectally or parenterally, for the relief and removal of pains of varying origin and for the treatment of rheumatic and other inflammatory diseases.

Compounds of Formula I are produced by reacting a compound of Formula II wherein R is lower alkyl, and R and R have the meanings given under Formula I,

With butadiene and hydrolysing the reaction product of Formula Ia wherein R R and R have the meanings given under Formulae I and II to the corresponding acid and converting, if desired, the acid so obtained into a salt with an inorganic or organic base.

The reaction of the nitroso compound of Formula II with butadiene is performed, for example, at temperatures between 0 and in an organic solvent such as chloroform, benzene or acetic acid, or in an excess of butadiene if necessary in a closed vessel. The optionally subsequent hydrolysis is carried out in the usual manner, e.g. by reacting the obtained compound of Formula Ia with an alkanolic aqueous alkali solution such as ethanolic sodium hydroxide solution preferably at room temperature.

The 2-(p-nitrosophenyl)-alkanolic acid alkyl esters of Formula II which are used as starting materials for the reaction sequence according to the invention, are new compounds. They are produced, for example, by the re duction of corresponding p-nitro compounds, e.g. by means of zinc dust in ethanol, to give p-hydroxyamino compounds, and partial reoxidation of the latter, e.g. by means of iron (III)-chloride in aqueous-ethanolic solution.

Optionally produceable pharmaceutically acceptable salts of the acids falling under Formula I are derived from inorganic and organic bases via conventional methods. Such salts include, for example the sodium, potassium, lithium, magnesium, calcium and ammonium salts, as well as salts derived from ethylamine, triethylamine, 2-aminoethanol, 2,2'-iminodiethanol, Z-dimethylaminoethanol, 2- diethylaminoethanol, ethylene diamine, benzylamine, procaine, pyrrolidine, piperidine, morpholine, l-ethyl piperidine, 2-piperidinoethanol and basic ion exchangers.

For their intended uses the new compounds of Formula I, as well as the pharmaceutically acceptable salts of the acids of Formula I are administered orally, rectally or parenterially preferably in form of pharmaceutical compositions.

Pharmaceutical compositions according to the present invention contain, :as active ingredient, at least one compound of Formula I and/or a pharmaceutically acceptable salt of an acid embraced by Formula I in combination with an inert carrier and, if desired, other additives. The inventive compositions consist, preferably, of dosage unit forms Which are suitable for the oral, rectal or parenteral application of daily doses of 180 mg./kg. of a compound of the invention for mammals. Suitable dosage unit forms for the oral or rectal application, like drages, tablets, capsules, suppositories respectively, contain preferably 10 to 500 mg. of a compound of the invention.

In the abovenamed dosage unit forms, the amount of active ingredient is preferably between and 90%. For preparation of tablets or drage cores, one combines the active ingredients for instance with solid powder-like carriers such as lactose, saccharose, sorbitol or mannitol; starches such as potato starch, corn starch or amylopectin, highly dispersed silicon dioxide, additional laminaria pow der or citrus pulp powder, cellulose derivatives or gelatine, if desired with the addition of lubricating agents like magnesium or calcium stearate or polyethylene glycols and presses the mixture into the desired form.

The drage cores are coated, for instance, with concentrated sugar solutions which can also contain arabic gum, talc and/or titanium dioxide or with a light volatile organic solvent or solvent mixture which contains dissolved varnish. To these coatings can be added pigments, for instance, to indicate different dosages of active substance. As other oral dosage unit forms, there are most suitable plugged capsules from gelatine and soft closed capsules from gelatine and a softening agent like glycerin. The first named contain the active ingredient, preferably as granulate, if desired in mixture with diluting agents like corn starch, with lubricating agents, like talc or magnesium stearate, and if desired, stabilisers, like sodium metabisulfite (Na S O or ascorbic acid. In soft capsules the active ingredient is preferably dissolved or suspended in suitable fluids, such as liquid polyethylene glycols, whereby, if desired, stabilisers can be added.

As dosage unit forms for the rectal application, are suitable, for instance, suppositories which consist of a combination of a compound of Formula I or a pharmaceutically acceptable salt of an acid embraced by Formula I, with a suppositorial ground mass, for instance, natural or synthetic triglycerides, or also gelatine rectal capsules which contain a combination of the active ingredient with polyethylene glycols.

Ampoule solutions for parenteral, especially intramuscular or intravenous administration contain, e.g. a compound of Formula I in a concentration of preferably 0.55% as an aqueous dispersion prepared with the aid of the usual dissolving agents and/or emulsifying agents as well as, optionally, stabilisers, or they contain an aqueous solution of a pharmaceutical acceptable, water solu ble salt of a free acid embraced by Formula I.

Other suitable dosage units for parenteral administration are, e.g. lotions, tinctures and ointments, prepared with the usual auxiliary agents, for percutaneous application.

As mentioned above, the present invention relates also to methods of alleviating pain and treating inflammatory diseases in mammals which methods comprise administering an effective amount of at least one compound of the invention, preferably in form of an inventive pharmaceutical composition.

It is to be understood that the dosage administered will be dependent on the species, the age, health and weight of the recipient; the severity of the condition being treated; the kind of concurrent treatment, if any; the frequency of treatment and the nature of the effect desired. Generally, the daily dosage of an active compound of Formula I will be from about 1 to about mg./ kg. of bodyweight. A preferred range is from about 1 to about 60 mg./ kg. of .bodyweight per day.

The following examples will serve to further typify the nature of the present invention, but should not be construed as a limitation on the scope thereof.

Temperatures are given in degrees Centigrade.

EXAMPLE 1 58.0 g. of (p-nitrosophenyl)-acetic acid ethyl ester and 50 ml. of butadiene are dissolved in 300 m1. of chloroform and the solution is allowed to stand for 30 hours at 0. The reaction mixture is then concentrated by evaporation under 10 torr on a water-bath at 20. The oily residue of 80 g. is crystallised from 550 ml. of petroleum ether (B.P. 50)/ether (3:2), by cooling of the solution to -25 during ca. 15 hours. The [p-(3,6-dihydro-2H- 1,2-oxazin-2-yl)-phenyl]acetic acid ethyl ester, M.P. 32- 34, is obtained. A specimen distilled for the analysis (B.P. 128130/0.1 torr), melts at 35-36", n =l.5448.

The ethyl ester required as starting material is produced as follows:

31.5 g. of (p-nitrophenyl)-acetic acid ethyl ester and 6.0 g. of calcium chloride are dissolved in 420ml. of 99% ethanol and 150 ml. of water. The solution is heated, while stirring, to boiling and 50 g. of zinc dust are introduced at this temperature within 10 minutes. The reaction mixture is then refluxed for 15 minutes and filtered hot. The filtrate is washed twice with 75 ml. of ethanol each time. The filtrate and washing liquid are mixed, still hot, together with 375 ml. of water.

The obtained clear solution, which contains the (p-hydroxyamino-phenyl) -acetic acid ethyl ester, is rapidly cooled to 5 and is then poured, while vigorously stirring, into a solution of g. of iron (III)-chloro-hexahydrate in 375 ml. of water at room temperature. A green solution is formed, from which the (p-nitrosophenyl)-acetic acid ethyl ester precipitates almost instantaneously in the form of yellow crystals. After 5 minutes the crystals are filtered off, thoroughly washed with water and dried for about 14 hours at 50. The (p-nitrosophenyl)-acetic acid ethyl ester, M.P. 7l-72, is obtained, and from this is obtained, by recrystallisation from water/acetic acid, the analytically pure substance, M.P. 72.

EXAMPLE 2 15.5 g. of 2-(p-nitrosophenyl)-butyric acid methyl ester and 19 ml. of butadiene are dissolved in 75 ml. of chloroform and the solution is allowed to stand for 17 hours at 0. The reaction mixture is then concentrated by evaporation on a water-bath at 75 under 10 torr. The addition product remaining as a residue in crystalline form, M.P. 53-55" (18.9 g., 96% of theoretical value) is crystallised from water-methanol (1:10) by cooling to 25 during 30 minutes, whereby 15.9 g. of 2-[p-(3,6-dihydro-2H-1,2-

oxazin-2-yl)-phenyl]-butyric acid methyl ester M.P. 57- 59, are obtained. A repeated recrystallisation of a specimen from water-methanol produces the analytically pure substance, M.P. 59-60.

The methyl ester required as starting material is produced as follows:

(a) 41.8 g. of 2-(p-nitrophenyl)-butyric acid are re fluxed in a mixture of 200 ml. of methanol and ml. of concentrated sulphuric acid for 4 hours. The reaction mixture is then intensively concentrated under 11 torr, cooled to 0 and poured, while stirring, into ice water. The precipitated 2-(p-nitrophenyD-butyric acid methyl ester is filtered off, washed with water and dried under 11 torr, M.P. 3335, yield 42.8 g.

(b) 33.5 g. of 2-(p-nitrophenyl)-butyric acid methyl ester and 48.0 g. of ammonium chloride are dissolved in 720 ml. of methanol and 225 ml. of water. 50 g. of Zinc dust are added in small portions, while vigorously stirring, within 20 minutes at room temperature and in a nitrogen atmosphere, whereby slight cooling is necessary. The reaction mixture is stirred for 15 minutes at room temperature and then it is poured through a filter with stirring at 0 into 53 ml. of 3 N hydrochloric acid. The filtrate is then washed with 80 ml. of methanolwater (1 :3).

Filtrate and washing liquid, which contain the crude hydrochloride of the 2-(p-hydr0xyamino-phenyl)-butyric acid methyl ester, are added dropwise at 7 within 10 minutes, while stirring, to a solution of 90 g. of iron (III)-chloride-hexahydrate in 375 ml. of water at 5". The solution turns green and the 2-(p-nitrosophenyl)- butyric acid methyl ester begins to precipitate immediately. After the addition is completed, the solution is stirred for a further 5 minutes at 5, whereupon the suspension is cooled to l5 and filtered. The reaction product, which is filtered off, is washed with 30 ml. of watermethanol (1:1) and then with water. The crystals are dried for hours at 40, whereby 21 g. of crude Z-(p-nitrosophenyl)-butyric acid methyl ester, M.P. 48 are obtained. By dissolving the product in 210 ml. of methanol at room temperature while stirring, filtering oil of the small amount of undissolved substance and leaving the solution to stand during 17 hours at 25, the 2-(p-nitrosophenyl)-butyric acid methyl ester, M.P. 48-52, are obtained, which is sufiiciently pure for further processing. An analytically pure substance, M.P. 5155, is obtained by further crystallisation from methanol.

EXAMPLE 3 A solution of 37.1 g. of [p-(3,6-dihydro-2H-1,2-oxazin- 2-yl)-phenyl]acetic acid ethyl ester [cf. Example 1] in 900 ml. of ethanol and 700 ml. of water is added to a solution of 7.4 g. of sodium hydroxide in 200ml. of water. The obtained emulsion is stirred at room temperature, whereby a clear solution is obtained after ca. 3 minutes. After stirring for one hour, 0.1 N hydrochloric acid is added until a pH value of 3.8 is obtained (ca. 1860 ml.) and the mixture is extracted four times with ether (500-160046004 300 ml.). Each extract is washed with 100 ml. of water. The extracts are then combined, dried over magnesium sulphate and concentrated by evaporation to dryness on a water-bath at under reduced pressure, finally 10 torr. The crystalline residue of M.P. 124-130 (with decomposition), consists of crude [p- (3,6 dihydro 2H 1,2 oxazin-2-yl)-phenyl]-acetic acid (78% of theoretical amount). By crystallisation from methanol-water (3:2) and then twice from benzene, the pure substance, M.P. 134-135 (with decomposition) are obtained.

EXAMPLE 4 2.61 g. of 2-[-(3,6-dihydr0-2H-1,2-oxazin-2-yl) -phenyl]-butyric acid methyl ester [cf. Example 2] are dissolved in 55 ml. of ethanol and 57 ml. of 0.39 N sodium hydroxide solution and the solution is allowed to stand at room temperautre for 24 hours. 0.18 N hydrochloric acid is then added to obtain a pH value of 2.2 (ca. 122 ml.). The obtained crystalline precipitate is filtered off, washed with 10 m1. of ethanol-water (1:3) and then twice with water and dried for one hour under 1 torr at 50. The 2-[p-(3,6-dihydro-2H-l,2-oxazin 2 yl)-phenyl]-butyric acid, M.P. 112-114, is obtained. A specimen for analysis, which is recrystallised from methanol-water (7:3), melts at 1 14-1 15 EXAMPLE 5 43.0 g. of 2-(3-chloro-4-nitroso-phenyl)-propionic acid methyl ester are added at -10" to a mixture of 48 ml. liquid butadiene and 190 ml. chloroform and left to stand for 16 hours at 0. After evaporation of the solvent by reduced pressure, the crude 2-[3-chloro-4-(3,6-dihydro- 2H 1,2 oxazin 2 yl)-phenyl]-propionic acid methyl ester is obtained as a red oil. This oil is purified in a bulb tube by distillation at 140/ 0.001 torr. After crystallisation from ligroine, colourless crystals are obtained with a melting point of 45-465 The 2 (3 chloro 4 nitrosophenyl)-propionic acid methyl ester used as starting material was prepared as follows:

(a) 101 g. methylmalonic acid diethyl ester was added dropwise with stirring over a period of 30 minutes at 25- 30 under nitrogen to a suspension of 13.9 g, of sodium hydride in 1300 ml. of dry N,N-dimethylformamide (DMF). The suspension was heated to and kept there for about 1 hour. When evolution of hydrogen had ceased, the almost clear solution of sodium methylmalonic ester was cooled to room temperature. 129 g. of 2,4-dichloronitrobenzene was added in one portion and the resulting red solution heated at 95 for 3 hours. During heating to 95 it was noticeable that the reaction was exothermic. The brown, turbid reaction mixture was evaporated to dryness from a water-bath under 10 mm. The oily residue was heated under reflux during 3 hours with 1160 ml. of ethanol, 580 ml. of water, and 93 g. of sodium hydroxide pellets. 900 ml. of water was added and the mixture distilled under 70 mm., until the distillation temperature was 50. About 2100 ml. of distillate was collected. The ethanol-free residue was cooled to 20 and extracted with five 250 ml. portions of ether. The aqueous phase was acidified to pH 2 with 180 .ml. of concentrated hydrochloric acid and the brown oil, which separated, extracted with two 500 ml. portions of ether. The combined ethereal extracts were washed with two 100 ml. portions of water to remove any DMF, dried with magnesium sulphate, and evaporated to dryness from a water bath (100) under 10 torr. The dark, oily residue was heated under reflux during 4 hours with 525 ml. of methanol and 20 ml. of concentrated sulphuric acid. The mixture was cooled to 10 and poured on a mixture of 900 g. of ice water. The resulting emulsion was extracted with ether (600+150 ml.), the ethereal solution was twice extracted with 150 ml. of 20% of potassium hydrogen carbonate solution and twice with 100 ml. of water, and dried with magnesium sulphate. Evaporation of the ether and distillation of the residue gave 2-(3-chloro-4-nitrophenyl)-propionic acid methyl ester as an orange-yellow oil (B 11 1.5448.

(b) 85 g. of 2-(3-chl0ro-4-nitro-phenyl)-propionic acid methyl ester and 113 g. of ammonium chloride were dissolved in 1690 ml. of methanol and 375 ml. of water. 116 g. of zinc powder were added in 5 g. portions under nitrogen over a period of 15 minutes at 2025 with stirring. After addition was complete the mixture was stirred for another 15 minutes at 20-25, cooled to 10, and filtered with suction. The filtered solution was added with stirring to 117 ml. of 3 N hydrochloric acid cooled to -5 to 10. The filter cake was washed with 250 ml. of water methanol of 0. The clear, light yellow filtrate (pH 1.52.0) containing the hydrochloride of 2-(3-chloro- 4-hydroxylamine-phenyl)-propionic acid methyl ester was added to a solution of iron (III) chloride [210 g. of iron (III) chloride hexahydrate in 685 ml. of water] with vigorous stirring at to over a period of 15 minutes. The green suspension was extracted three times with cold benzene (l500+500+500 ml.). The combined benzene extracts were washed at 0 with two 450 ml. portions of N hydrochloric acid, 400 ml. of water, two 450 ml. portions of 20% potassium hydrogen carbonate solution, and finally again two 400 ml. portions of water. The washed benzene extract was dried with magnesium sulphate and evaporated to dryness from a water bath (30) under torr. The 2-(3-chloro-4-nitroso-phenyl)-propionic acid methyl ester remains as a green oil.

EXAMPLE 6 45.6 g. of 2-[3-chloro-4-(3,6-dihydro-2H-1,2-0xazin-2- yl)-phenyl]-propionic acid methyl ester are stirred with a solution of g. of sodium hydroxide in 100 ml. water and 200 ml. of methanol for an hour at -30". After acidification with 145 ml. of 3 N hydrochloric acid, precipitates an oil. This oil is twice extracted with 500 ml. of ether and the whole ether extract is washed with 100 ml. of water, dried with magnesium sulphide and concentrated by evaporation under reduced pressure. -An oil is obtained which, after coo-ling, crystallises partially. After recrystallisation of methanol water, the 2-[3-chloro- 4- (3 ,6-dihydro-2H-1,2-oxazin-2-yl)phenyl] -propionic acid is obtained, melting point 160l70.

The following prescriptions further illustrate the production of various dosage units:

EXAMPLE 7 1000 g. of active substance, e.g. [p-(3,6-dihydro-2H- 1,2-oxazin-2-yl)phenyl]-acetic acid, are mixed with 550 g. of lactose and 292 g. of potato starch. The mixture is moistened with an alcoholic solution of 8 g. of gelatine and is granulated through a sieve. After drying, 60 g. of potato starch, 60 g. of talcum and 10 g. of magnesium stearate and 20 g. of highly dispersed silicon dioxide are mixed in. The mixture is then pressed into 10,000 tablets, each Weighing 200 mg. and each containing 100 mg. of active substance. Optionally, the tablets can be provided with grooves for more accurate adjustment of the dosage amount.

EXAMPLE 8 200 g. of active substance, e.g. [p-dihydro-2H-1,2- oxazin-2-yl)-phenyl] acetic acid ethyl ester are mixed with 16 g. of maize starch and 6 g. of highly dispersed silicon dioxide. The mixture is moistened with a solution of 2 g. of stearic acid, 6 g. of ethyl cellulose and 6 g. of stearin in ca. 70 ml. of isopropyl alcohol and is granulated through a sieve III (Ph. Hel-v. V). The granulate is dried for ca. 14 hours and is then pressed through sieve III-IIIa. It is then mixed with 16 g. of maize starch, 16 g. of talcum and 2 g. of magnesium stearate and pressed into 1000 drage cores. These are coated with a concentrated syrup of 2 g. of shellac, 7.5 g. of gum arabic, 0.15 g. of dyestufl, 2 g. of highly dispersed silicon dioxide, g. of talcum and 53.35 g. of sugar and dried. The obtained drages each Weigh 360 mg. and each contain 200 mg. of active substance.

EXAMPLE 9 50.0 g. of 2-[3-chloro-4-(3,6-dihydro-2H-1,2-oxazin-2- yl)-phenyl] -propionic acid are dissolved in a mixture of 218 ml. of 1 N sodium hydroxide solution and 500 ml. of boiled, pyrogen-free water and, with water treated in the same manner, the solution is then made up to 2000 ml. The solution is filtered and used to fill 1000 ampoules each containing 2 ml., and sterilised. A 2 ml. ampoule contains 50 mg. of 2- [p-1-pyrryl)-phenyl] -butyric acid as active substance in the form of the sodium salt.

EXAMPLE 10 50 g. of 2-[3-chloro-4-(3,6-dihydro-2H-1,2-oxazin-2- yl)-phenyl]-propionic acid and 1950 g. of finely ground suppository foundation substance (e.g. cocoa butter) are thoroughly mixed and then melted. The melt is maintained homogeneous by stirring and from it are made 1000 suppositories, each weighing 2 g. and each containing 50 mg. of active substance.

EXAMPLE 11 60.0 g. of polyoxyethylene-sorbitan monostearate, 30.0 g. of sorbitan-monostearate, 150.0 g. of paraffin oil and 120.0 g. of stearyl alcohol are melted together. 50.0 g. of [p-(3-dihydro-2H-1,2-oxazin-2-yl)-phenyl]-acetic acid (finely pulverised) are then added and 590 m1. of water, preheated to 40, are used to form an emulsion. The emulsion is stirred until it has cooled to room temperature and is then poured into tubes.

What We claim is:

1. A compound of the Formula I O I R1 wherein R is hydrogen, methyl or ethyl,

R is hydrogen or halogen up to the atomic number 35,

and

R is hydrogen, methyl or ethyl,

or a pharmaceutically acceptable salt of a compound of Formula I, wherein R is hydrogen.

2. A compound according to claim 1, wherein R is hydrogen or methyl, R is hydrogen or chloro and R is hydrogen, or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, which is [p-(3,6- dihydro-2H-1,2-oxazin-2-yl)-phenyl]-acetic acid or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1, which is 2-[3- chloro 4 (3,6 dihydro-2H-1,2-oxazin-2-yl)-phenyl]- propionic acid or a pharmaceutically acceptable salt thereof.

References Cited UNITED STATES PATENTS 6/1933 Salzberg et al. 260-243 3/1937 Salzberg et a1. 424-250 US. Cl. X.R. 

